Aim: Obesity increases the risk for aggressive and fatal prostate cancer (PCa). The bioactive compound silibinin has been researched for its chemopreventative properties and may benefit obese or overweight individuals with PCa.Methods: This study used an in vitro model of obesity exposing prostate cancer cells to sera from obese, overweight, or normal weight males with or without the addition of silibinin. Molecular activity was assayed as well as the phenotype of PCa cells with various treatments.Results: Obesity increased the expression of proliferative signaling including COX-2, IL-6, AKT, ERK, and AR, which was attenuated with silibinin. Cell growth, and invasive capacity of prostate cancer cells was increased with obese and overweight sera, and silibinin was able to mitigate this affect. However, there are limitations to this study in that an in vivo model was not used to validate these in vitro results nor a co-culture model, which may better recapitulate the tumor microenvironment.Conclusions: Silibinin may be a safe intervention for those with or at risk for prostate cancer, and it may be the most beneficial for obese or overweight males.